FTDP-17 mutations in Tau alter the regulation of microtubule dynamics: an "alternative core" model for normal and pathological Tau action.
Mutations affecting either the structure or regulation of the microtubule-associated protein Tau cause neuronal cell death and dementia. However, the molecular mechanisms mediating these deleterious effects remain unclear. Among the most characterized activities of Tau is the ability to regulate microtubule dynamics, known to be essential for proper cell function and viability. Here we have tested the hypothesis that Tau mutations causing neurodegeneration also alter the ability of Tau to regulate the dynamic instability behaviors of microtubules. Using in vitro microtubule dynamics assays to assess average microtubule growth rates, microtubule growth rate distributions, and catastrophe frequencies, we found that all tested mutants possessing amino acid substitutions or deletions mapping to either the repeat or interrepeat regions of Tau do indeed compromise its ability to regulate microtubule dynamics. Further mutational analyses suggest a novel mechanism of Tau regulatory action based on an "alternative core" of microtubule binding and regulatory activities composed of two repeats and the interrepeat between them. In this model, the interrepeat serves as the primary regulator of microtubule dynamics, whereas the flanking repeats serve as tethers to properly position the interrepeat on the microtubule. Importantly, since there are multiple interrepeats on each Tau molecule, there are also multiple cores on each Tau molecule, each with distinct mechanistic capabilities, thereby providing significant regulatory potential. Taken together, the data are consistent with a microtubule misregulation mechanism for Tau-mediated neuronal cell death and provide a novel mechanistic model for normal and pathological Tau action.
LeBoeuf
Adria C
AC
Neuroscience Research Institute and Department of Molecular and Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
Levy
Sasha F
SF
Gaylord
Michelle
M
Bhattacharya
Arnab
A
Singh
Ambuj K
AK
Jordan
Mary Ann
MA
Wilson
Leslie
L
Feinstein
Stuart C
SC
D000595:Amino Acid Sequence; D002470:Cell Survival; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
D018076:DNA, Complementary; C054369:MAPT protein, human; D020033:Protein Isoforms; D014404:Tubulin; D016875:tau Proteins